Digital Commons Network^™

Genetic Variants In Immune Related Genes As Predictors Of Responsiveness To Bcg Immunotherapy In Metastatic Melanoma Patients., Romela Irene Ramos, Misa A Shaw, Leland J Foshag, Stacey L Stern, Negin Rahimzadeh, David Elashoff, Dave Hoon

Articles, Abstracts, and Reports

Adjuvant immunotherapy in melanoma patients improves clinical outcomes. However, success is unpredictable due to inherited heterogeneity of immune responses. Inherent immune genes associated with single nucleotide polymorphisms (SNPs) may influence anti-tumor immune responses. We assessed the predictive ability of 26 immune-gene SNPs genomic panels for a clinical response to adjuvant BCG (Bacillus Calmette-Guérin) immunotherapy, using melanoma patient cohorts derived from three phase III multicenter clinical trials: AJCC (American Joint Committee on Cancer) stage IV patients given adjuvant BCG (pilot cohort; n = 92), AJCC stage III patients given adjuvant BCG (verification cohort; n = 269), and …

Metabolic Network Analysis Reveals Altered Bile Acid Synthesis And Metabolism In Alzheimer's Disease., Priyanka Baloni, Cory C Funk, Jingwen Yan, James T Yurkovich, Alexandra Kueider-Paisley, Kwangsik Nho, Almut Heinken, Wei Jia, Siamak Mahmoudiandehkordi, Gregory Louie, Andrew J Saykin, Matthias Arnold, Gabi Kastenmüller, William J Griffiths, Ines Thiele, Alzheimer’S Disease Metabolomics Consortium, Rima Kaddurah-Daouk, Nathan D Price

Articles, Abstracts, and Reports

Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. …

A Pilot Study Comparing The Efficacy Of Lactate Dehydrogenase Levels Versus Circulating Cell-Free Micrornas In Monitoring Responses To Checkpoint Inhibitor Immunotherapy In Metastatic Melanoma Patients., Matias A Bustos, Rebecca Gross, Negin Rahimzadeh, Hunter Cole, Linh T Tran, Kevin Tran, Ling Takeshima, Stacey L Stern, Steven O'Day, Dave Hoon

Articles, Abstracts, and Reports

Serum lactate dehydrogenase (LDH) is a standard prognostic biomarker for stage IV melanoma patients. Often, LDH levels do not provide real-time information about the metastatic melanoma patients' disease status and treatment response. Therefore, there is a need to find reliable blood biomarkers for improved monitoring of metastatic melanoma patients who are undergoing checkpoint inhibitor immunotherapy (CII). The objective in this prospective pilot study was to discover circulating cell-free microRNA (cfmiR) signatures in the plasma that could assess melanoma patients' responses during CII. The cfmiRs were evaluated by the next-generation sequencing (NGS) HTG EdgeSeq microRNA (miR) Whole Transcriptome Assay (WTA; 2083 …

Brainstem Ischemic Syndrome In Juvenile Nf2., John W Henson, Tara Benkers, Connor Mccormick

Articles, Abstracts, and Reports

Objective: A new case of brainstem ischemic necrosis in a young woman with de novo neurofibromatosis type 2 (NF2) is reported, and given notable similarities to 7 prior cases of brainstem stroke in the literature, features defining a possible syndrome were sought.

Methods: Case review including detailed clinical assessment, neuroimaging analysis, genetic testing, and brain biopsy, followed by a multicase analysis.

Results: Brainstem ischemia in juvenile NF2 typically occurs in teenagers without previously known NF2 as an acute, monophasic presentation with restricted diffusion in the midbrain or pons following a recent hypoperfusion event, normal vascular imaging, obvious intracranial imaging features …

Congenital Myasthenic Syndrome Caused By A Frameshift Insertion Mutation In, Szabolcs Szelinger, Jonida Krate, Keri Ramsey, Samuel P Strom, Perry B Shieh, Hane Lee, Newell Belnap, Chris Balak, Ashley L Siniard, Megan Russell, Ryan Richholt, Matt De Both, Ana M Claasen, Isabelle Schrauwen, Stanley F Nelson, Matthew J Huentelman, David W Craig, Samuel Yang, Steven A Moore, Kumaraswamy Sivakumar, Vinodh Narayanan, Sampathkumar Rangasamy, Ucla Clinical Genomics Center

Articles, Abstracts, and Reports

Objective: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families.

Methods: Muscle biopsies, EMG, and whole-exome sequencing were performed.

Results: All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the GFPT1 gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent …

Meta-Analysis Of The Alzheimer's Disease Human Brain Transcriptome And Functional Dissection In Mouse Models., Ying-Wooi Wan, Rami Al-Ouran, Carl G Mangleburg, Thanneer M Perumal, Tom V Lee, Katherine Allison, Vivek Swarup, Cory C Funk, Chris Gaiteri, Mariet Allen, Minghui Wang, Sarah M Neuner, Catherine C Kaczorowski, Vivek M Philip, Gareth R Howell, Heidi Martini-Stoica, Hui Zheng, Hongkang Mei, Xiaoyan Zhong, Jungwoo Wren Kim, Valina L Dawson, Ted M Dawson, Ping-Chieh Pao, Li-Huei Tsai, Jean-Vianney Haure-Mirande, Michelle E Ehrlich, Paramita Chakrabarty, Yona Levites, Xue Wang, Eric B Dammer, Gyan Srivastava, Sumit Mukherjee, Solveig K Sieberts, Larsson Omberg, Kristen D Dang, James A Eddy, Phil Snyder, Yooree Chae, Sandeep Amberkar, Wenbin Wei, Winston Hide, Christoph Preuss, Ayla Ergun, Phillip J Ebert, David C Airey, Sara Mostafavi, Lei Yu, Hans-Ulrich Klein, Accelerating Medicines Partnership, Alzheimer’S Disease Consortium, Gregory W Carter, David A Collier, Todd E Golde, Allan I Levey, David A Bennett, Karol Estrada, T Matthew Townsend, Bin Zhang, Eric Schadt, Philip L De Jager, Nathan D Price, Nilüfer Ertekin-Taner, Zhandong Liu, Joshua M Shulman, Lara M Mangravite, Benjamin A Logsdon

Articles, Abstracts, and Reports

We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic …

Inter-Tumor Heterogeneity-Melanomas Respond Differently To Gm-Csf-Mediated Activation., Adi Moshe, Sivan Izraely, Orit Sagi-Assif, Sapir Malka, Shlomit Ben-Menachem, Tsipi Meshel, Metsada Pasmanik-Chor, Dave Hoon, Isaac P Witz

Articles, Abstracts, and Reports

Granulocyte-monocyte colony stimulating factor (GM-CSF) is used as an adjuvant in various clinical and preclinical studies with contradictory results. These were attributed to opposing effects of GM-CSF on the immune or myeloid systems of the treated patients or to lack of optimal dosing regimens. The results of the present study point to inter-tumor heterogeneity as a possible mechanism accounting for the contrasting responses to GM-CSF incorporating therapies. Employing xenograft models of human melanomas in nude mice developed in our lab, we detected differential functional responses of melanomas from different patients to GM-CSF both in vitro as well as in vivo. …

Advancing Human Health In The Decade Ahead: Pregnancy As A Key Window For Discovery: A Burroughs Wellcome Fund Pregnancy Think Tank., Yoel Sadovsky, Sam Mesiano, Graham J Burton, Michelle Lampl, Jeffrey C Murray, Rachel M Freathy, Anita Mahadevan-Jansen, Ashley Moffett, Nathan D Price, Paul H Wise, Derek E Wildman, Ralph Snyderman, Nigel Paneth, John Anthony Capra, Marcelo A Nobrega, Yaacov Barak, Louis J Muglia

Articles, Abstracts, and Reports

Recent revolutionary advances at the intersection of medicine, omics, data sciences, computing, epidemiology, and related technologies inspire us to ponder their impact on health. Their potential impact is particularly germane to the biology of pregnancy and perinatal medicine, where limited improvement in health outcomes for women and children has remained a global challenge. We assembled a group of experts to establish a Pregnancy Think Tank to discuss a broad spectrum of major gestational disorders and adverse pregnancy outcomes that affect maternal-infant lifelong health and should serve as targets for leveraging the many recent advances. This report reflects avenues for future …

The Society For Immunotherapy Of Cancer Statement On Best Practices For Multiplex Immunohistochemistry (Ihc) And Immunofluorescence (If) Staining And Validation., Janis M Taube, Guray Akturk, Michael Angelo, Elizabeth L Engle, Sacha Gnjatic, Shirley Greenbaum, Noah F Greenwald, Cyrus V Hedvat, Travis J Hollmann, Jonathan Juco, Edwin R Parra, Marlon C Rebelatto, David L Rimm, Jaime Rodriguez-Canales, Kurt A Schalper, Edward C Stack, Cláudia S Ferreira, Konstanty Korski, Ana Lako, Scott J Rodig, Emanuel Schenck, Keith E Steele, Michael J Surace, Michael T Tetzlaff, Katharina Von Loga, Ignacio I Wistuba, Carlo Bifulco, Society For Immunotherapy Of Cancer (Sitc) Pathology Task Force.

Articles, Abstracts, and Reports

OBJECTIVES: The interaction between the immune system and tumor cells is an important feature for the prognosis and treatment of cancer. Multiplex immunohistochemistry (mIHC) and multiplex immunofluorescence (mIF) analyses are emerging technologies that can be used to help quantify immune cell subsets, their functional state, and their spatial arrangement within the tumor microenvironment.

METHODS: The Society for Immunotherapy of Cancer (SITC) convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to develop best practice guidelines for the optimization and validation of mIHC/mIF assays across platforms.

RESULTS: Representative outputs …